Traditionally, the muscle-bone relationship has been assumed to be driven mainly by mechanical factors. Nevertheless, based on observations that bone can act as an endocrine organ, that muscle can produce regulatory 'myokines', and our new preliminary data, we propose in this application that bone and muscle act as endocrine organs that influence each other in health and disease. We found that mice with the Lrp5 mutation leading to a high bone mass phenotype, showed enhanced cardiovascular contractile function compared to control mice, but unexpectedly impaired skeletal muscle contractile force. This led to the paradigm-shifting hypothesis that bone can act as an endocrine organ, sending regulatory signals to muscles, whether skeletal, smooth, or cardiac, and that a reciprocal relationship also exists by which muscle can regulate bone mass and strength independent of mechanical loading. This hypothesis of a bone-muscle endocrine axis will be tested using both whole organism and in vitro approaches as outlined in two specific aims: Specific Aim 1. To determine if bone can regulate muscle mass, strength, and contractile function and Specific Aim 2. To determine if muscle can regulate bone mass and function independent of mechanical loading. Two teams of investigators, one in the field of bone biology and one in the field of muscle biology, will utilize the tools, approaches, and combined expertise to work collaboratively towards accomplishing these aims. This newly proposed Muscle-Bone Endocrine Research Group will be supported by the existing infrastructure of our various departments and by the UMKC Center for the Study of Mineralized Tissue. Our work is innovative and ground-breaking and can be readily deployed to accelerate research in this area. Establishment of our research team and the accomplishment of these goals will have high impact with regards to musculoskeletal disease. For example, sarcopenia and osteoporosis are serious health threats among the elderly and are the major causes for debilitating injuries, loss of independence, and reduced quality of life. The potential reciprocal consequences of muscle and bone diseases and how they influence overall health and disease during aging are not known. Therefore, this new line of research should have high impact, and may lead to the discovery of new factors that could be targets of therapeutic intervention for the prevention of bone and muscle diseases.